Randomized controlled trials suggest that ADHD medication has beneficial short-term effects. The increasing use of ADHD medications is being heavily debated, however, because of concerns regarding the short- and long-term effects of ADHD medications. The overall objective for this proposal is to more precisely estimate the magnitude of the short- and long-term risks and benefits of ADHD medications on serious psychiatric (substance abuse, suicidal behavior, mania/bipolar disorder, and major depression) and neurological (seizures/epilepsy) outcomes by conducting advanced pharmaco-epidemiologic analyses in two large datasets that include prospective longitudinal information on prescribed ADHD medications and medical problems. We will use a Swedish cohort of 75,000 patients with a diagnosis of ADHD based on national registers. And, we will conduct analyses on a large US sample based on insurance claims, including 2.3 million patients with ADHD. The analyses in both datasets will use the same analytical approaches, including within-individual comparisons and advanced statistical techniques to account for stable and time-varying confounding. Our central hypothesis is that ADHD medication will be associated with reduced psychiatric and neurological problems and that risk for adverse outcomes (e.g., short-term seizures and long-term substance use problems) will be minor, especially when we compare the relations within individuals. The first aim is to examine the short-term effects of ADHD medications on these problems. The second aim is to examine the long-term effects of ADHD medications on these problems. The rationale for the proposed research is that rigorous pharmaco-epidemiologic studies-employing advanced designs and statistical analyses with large, population samples-can more precisely characterize the risks and benefits of ADHD medication. The significance of the proposed research is that the results will more precisely identify the specific risks and benefits associated with ADHD medication, which previous studies have been unable to adequately explore. The proposed analyses, which are based on the two large datasets, also will explore the generalizability of the findings across different national, cultural, and medical contexts. These efforts would directly inform medical practice and influence subsequent research in numerous fields, such as pharmaco-epidemiology and randomized controlled trials. The proposed research is innovative because the research team will analyze two datasets (in Sweden and the United States); combine within-individual comparisons with sophisticated analytical strategies to rule out confounding factors; and bring together a team of international researchers with expertise in the etiology and treatment of ADHD, pharmaco-epidemiology, quasi-experimental designs, and analyses of both datasets. We propose, therefore, to conduct the most comprehensive study of serious psychiatric and neurologic problems associated with ADHD medication to date.